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HARRISON'S PRINCIPLES OF INTERNAL MEDICINE

Complete Notes: Chapters 23-31, 33

Neurological Symptoms - The Full Clinical Picture

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CHAPTER 23 - SYNCOPE

Definition and Core Concept

Epidemiology

• Neurally mediated (reflex) syncope: most common cause overall; higher incidence in women; often familial
• Cardiac syncope: next most common, especially in ED settings and older patients
• Orthostatic hypotension: prevalence increases with age
• Syncope of noncardiac/unexplained origin in the young: excellent prognosis, life expectancy unaffected
• Cardiac syncope: associated with increased risk of sudden cardiac death

Pathophysiology

• Chronically → orthostatic hypotension
• Transiently → neurally mediated syncope

HIGH-RISK FEATURES - Hospitalization Required

Causes of Syncope (Table 23-2)

A. Neurally Mediated (Reflex) Syncope

• Triggered by: prolonged standing, warm environment, emotional stress, pain, blood/needle phobia
• Prodrome: nausea, warmth, diaphoresis, pallor, yawning
• Mechanism: ventricular mechanoreceptor activation → vagal surge (Bezold-Jarisch reflex)
• Recovery: rapid, supine position
• Treatment: education, avoid triggers, physical counter-pressure maneuvers (leg crossing, arm tensing), increased salt/fluid intake, beta-blockers (selected patients), midodrine, fludrocortisone. A 2021 RCT showed midodrine reduces vasovagal syncope recurrence.

• Micturition syncope (post-void, especially at night in men)
• Cough syncope (Valsalva-like mechanism)
• Deglutition syncope (swallowing cold liquids)
• Defecation syncope
• Carotid sinus hypersensitivity: syncope with head turning, tight collar; >3-second pause or >50 mmHg BP drop on carotid sinus massage → diagnostic

B. Orthostatic Hypotension

• Defined: systolic BP drop ≥20 mmHg or diastolic ≥10 mmHg within 3 minutes of standing
• Causes: autonomic neuropathy (diabetes, amyloid, Parkinson's), medications (antihypertensives, diuretics, alpha-blockers), dehydration, adrenal insufficiency
• Delayed orthostatic hypotension: BP drop occurs after 3-10 minutes - check at multiple time points
• Treatment: volume expansion, compression stockings, raise head of bed, fludrocortisone, midodrine, droxidopa (for neurogenic OH)

C. Cardiac Syncope

• Arrhythmias: bradyarrhythmias (sick sinus syndrome, AV block), tachyarrhythmias (VT, SVT with rapid ventricular rate), channelopathies (long QT, Brugada, CPVT)
• Structural: aortic stenosis (exertional syncope = critical sign), HCM, pulmonary hypertension, cardiac tamponade, acute MI
• Key feature: usually no prodrome, often occurs during exertion or lying down, rapid recovery

Evaluation

1. Detailed history - character of episode, position, activity, prodromes, duration, post-event
2. Physical examination - orthostatic BP, cardiac exam, neurologic exam
3. 12-lead ECG

• Holter/ambulatory ECG: when arrhythmia suspected but not documented
• Implantable loop recorder: recurrent unexplained syncope; diagnostic yield highest over months
• Echocardiogram: if structural heart disease suspected
• Tilt-table test: for suspected vasovagal/orthostatic; sensitivity 26-80%, specificity 90%
• Exercise stress test: syncope during or immediately after exertion
• Electrophysiology study: for suspected arrhythmic syncope, especially in structural heart disease
• Carotid sinus massage: for suspected carotid hypersensitivity (avoid if carotid bruits or recent TIA/stroke)
• Brain MRI/CT: NOT routinely indicated; only if focal neurologic signs suggest structural lesion

Treatment Overview

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CHAPTER 24 - DIZZINESS AND VERTIGO

Core Definitions

1. Is it dangerous (arrhythmia, TIA/stroke)?
2. Is it vestibular?
3. If vestibular - peripheral or central?

Classification

1. Vestibular Dizziness

2. Presyncope / Cardiovascular Dizziness

3. Non-vestibular Balance/Gait Disorders

4. Anxiety-Related Dizziness

History Taking

• Seconds: BPPV (position-triggered), superior canal dehiscence, otolith dysfunction
• Minutes to hours: TIA (vascular), Meniere's disease
• Days: acute vestibular neuritis/labyrinthitis, cerebellar infarct
• Constant/chronic: bilateral vestibulopathy, PPPD (functional)

• Position change (rolling in bed, looking up): BPPV
• Upright posture: presyncope/orthostasis
• Head movement in any direction: bilateral vestibulopathy
• Loud sound or pressure (Valsalva): superior canal dehiscence
• Stress, crowded places, screens: PPPD

• Hearing loss + tinnitus + fullness: Meniere's disease
• Diplopia, dysphagia, dysarthria, facial numbness: posterior fossa/brainstem lesion - DANGER
• Hearing loss alone: cochlear/labyrinthine pathology
• Headache: migraine-associated vertigo or posterior fossa hemorrhage

Examination

• Head Impulse test - Nystagmus pattern - Test of Skew
• Negative HIT (normal VOR) + direction-changing nystagmus + skew deviation = central (stroke) - requires urgent imaging
• Positive HIT (corrective saccade) + unidirectional nystagmus + no skew = peripheral (vestibular neuritis)
• HINTS has higher sensitivity for posterior fossa stroke than early MRI DWI (which can be falsely negative in first 24-48h)

• Patient moved from sitting to lying with head turned 45°
• Positive: latency 1-5 seconds, then upbeat-torsional nystagmus, fatiguable, reverses on return to sitting
• Indicates posterior semicircular canal BPPV (most common type)

Specific Vestibular Disorders

BPPV (Benign Paroxysmal Positional Vertigo)

• Most common cause of vertigo overall
• Pathology: otoconia (calcium carbonate crystals) dislodged from utricle → enter semicircular canals (usually posterior canal)
• Symptoms: brief (seconds) intense vertigo with specific head position changes
• Diagnosis: Dix-Hallpike (posterior canal BPPV) or supine roll test (horizontal canal)
• Treatment: Epley canalith repositioning maneuver - highly effective (1-2 treatments), first-line. No medications needed. Semont maneuver is alternative.

Vestibular Neuritis (Labyrinthitis)

• Acute prolonged vertigo (days), usually viral (HSV-1 reactivation)
• No hearing loss (neuritis) vs. hearing loss (labyrinthitis)
• Intense vertigo, nausea/vomiting, postural instability
• Exam: unidirectional spontaneous horizontal-torsional nystagmus, fast phase AWAY from the affected ear; positive HIT on affected side
• Treatment: Acute phase: vestibular suppressants (meclizine, diazepam) for up to 3 days only. Longer use delays central compensation. Methylprednisolone (not antivirals) reduces long-term deficit. Vestibular rehabilitation exercises accelerate recovery.

Meniere's Disease (Endolymphatic Hydrops)

• Triad: episodic vertigo (minutes to hours) + fluctuating low-frequency sensorineural hearing loss + tinnitus + aural fullness
• Pathology: excess endolymph in membranous labyrinth
• Diagnosis: clinical (audiogram showing low-frequency SNHL)
• Treatment: Low-salt diet (<2g/day), diuretics (hydrochlorothiazide-triamterene), betahistine. Severe cases: intratympanic gentamicin ablation or endolymphatic shunt surgery.

Central Vertigo - DANGER Signs (STROKE)

• Sudden onset severe vertigo + headache + ANY neurologic sign
• Purely vertical nystagmus (upbeat or downbeat)
• Direction-changing nystagmus
• Normal head impulse test with spontaneous nystagmus
• Skew deviation (vertical eye misalignment)
• Dysphagia, diplopia, dysarthria, facial numbness
• Management: Urgent non-contrast CT (to exclude hemorrhage) → MRI with DWI → treat as posterior circulation stroke

Migraine-Associated Vertigo (Vestibular Migraine)

• Most common cause of episodic vertigo in young patients
• Vertigo can occur with, before, or without headache
• Diagnosis: recurrent vertigo + migraine history, excluding other causes
• Treatment: migraine prophylaxis (topiramate, amitriptyline, beta-blockers)

Functional Dizziness (PPPD)

• Persistent (>3 months), non-spinning dizziness, worsened by upright posture, movement, visual stimuli
• Often follows an initial vestibular event (BPPV, neuritis, panic attack)
• No nystagmus, normal neurologic exam
• Treatment: SSRIs/SNRIs, vestibular rehabilitation, CBT

Vestibular Suppressants (for acute phase only)

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CHAPTER 26 - WEAKNESS AND PARALYSIS

Terminology

• Paresis = partial loss of motor function
• Plegia/Paralysis = complete loss of motor function
• Monoparesis = one limb
• Paraparesis = both legs
• Hemiparesis = one side (arm + leg)
• Quadriparesis/Tetraparesis = all four limbs
• Fatigable weakness = neuromuscular junction (myasthenia gravis)

Motor System Organization

Upper Motor Neurons (UMN)

• 10-30% remain ipsilateral in anterior corticospinal tract
• Most dense innervation: hand muscles (fine, learned movements)
• Corticobulbar neurons: same pathway but innervate brainstem motor nuclei (CN III-XII)

• Tectospinal (midbrain tectum): axial muscles
• Vestibulospinal (vestibular nuclei): postural stability, proximal extensors
• Reticulospinal (reticular formation): axial + proximal muscles
• Rubrospinal (red nucleus): distal limb muscles
• These facilitate axial/proximal muscles, maintain posture, integrate limb/trunk movements

Lower Motor Neurons (LMN)

• Alpha motor neurons in spinal anterior horn (and cranial nerve motor nuclei)
• Each alpha motor neuron + muscle fibers it innervates = motor unit
• Innervation ratio: small muscles (e.g., extraocular) = few fibers per neuron (fine control); large muscles (e.g., quadriceps) = thousands of fibers per neuron (strength)
• Motor unit activation = all-or-none

UMN vs LMN Signs

Neuromuscular Junction Weakness

• Weakness of variable degree; varies with activity
• Myasthenia gravis: sustained/repeated contractions → declining strength despite continuing effort = fatigable weakness; anti-AChR or anti-MuSK antibodies
• Lambert-Eaton: proximal weakness improves with repeated activity (opposite of MG); associated with SCLC; P/Q-type VGCC antibodies

Myopathic Weakness

• Decreased number or contractile force of muscle fibers
• Muscular dystrophies, inflammatory myopathies (polymyositis, dermatomyositis), myopathies with necrosis
• EMG: decreased motor unit action potential size, rapid recruitment
• Proximal > distal distribution typical; preserved reflexes until late

Distribution of Weakness - Anatomic Localization

Hemiplegia

• Contralateral cortex or internal capsule: face + arm + leg on same side
• Cortical lesion: often arm > leg; may have aphasia/neglect/hemianopia
• Internal capsule: dense equal face/arm/leg; no cortical signs
• Brainstem: ipsilateral CN palsy + contralateral hemiplegia (crossed syndrome)

Paraplegia

• Spinal cord lesion (thoracic most common)
• UMN signs below lesion level
• Associated: sensory level, bladder/bowel dysfunction
• Causes: MS, cord compression (tumor, disc, epidural abscess/hematoma), transverse myelitis, cord infarction

Quadriplegia

• High cervical cord: UMN all four limbs (may have diaphragm involvement if C3-C5)
• Lower cervical cord: LMN arms + UMN legs (due to cervical enlargement)

Monoplegia

• Cortical lesion: contralateral arm or leg (not both)
• Peripheral: single nerve or plexus

Distal > Proximal Weakness

• Peripheral polyneuropathy (length-dependent)
• Myotonic dystrophy

Proximal > Distal Weakness

• Myopathy (typical)
• Inflammatory myopathy
• Some muscular dystrophies (Duchenne, Becker, LGMD)

Fatigable Weakness

• Neuromuscular junction disorder (MG, Lambert-Eaton)

Episodic Weakness (Table 26-2 Causes)

• Periodic paralyses (hypokalemic, hyperkalemic, Andersen-Tawil)
• Transient ischemic attacks
• Multiple sclerosis exacerbations
• Myasthenia gravis crisis
• Metabolic myopathies (exercise-induced)

Acute Severe Weakness - Emergencies

• Back pain + leg weakness + sensory level + bladder retention
• MRI urgently, high-dose dexamethasone, radiation/surgery

• Ascending flaccid paralysis + areflexia, often post-infectious (Campylobacter, CMV, EBV, Zika)
• CSF: albuminocytologic dissociation (elevated protein, normal WBC)
• Electrophysiology: demyelinating (AIDP) or axonal (AMAN, AMSAN)
• Treatment: IVIG or plasmapheresis; monitor respiratory (FVC <20 mL/kg = intubate)

• Respiratory failure from MG; triggered by infection, medications
• Treatment: IVIG or plasmapheresis, mechanical ventilation

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CHAPTER 27 - NUMBNESS, TINGLING, AND SENSORY LOSS

Sensory Symptom Classification

Positive Symptoms (excess activity in sensory pathway)

• Tingling (pins and needles), paresthesias
• Itch, pricking, lancinations, burning, electrical, raw
• May be painful
• NOT necessarily associated with sensory deficit on exam
• Represent ectopic impulse generation at sites of lowered threshold

Negative Symptoms (loss of sensory function)

• Numbness, reduced/absent sensation
• Always a deficit on examination
• Require loss of >50% of afferent axons before clinically detectable

Terminology (Must Know)

Sensory Pathways - Anatomy

Dorsal Column-Medial Lemniscal Pathway (Fine Touch, Proprioception, Vibration)

Spinothalamic Tract (Pain, Temperature, Crude Touch)

• IPSILATERAL loss of proprioception/vibration (dorsal column)
• CONTRALATERAL loss of pain/temperature (spinothalamic) - one level below lesion

Brown-Sequard Syndrome (Cord Hemisection)

• Ipsilateral: UMN weakness + loss of proprioception/vibration
• Contralateral: loss of pain and temperature (1-2 levels below lesion)
• Causes: trauma, tumor, MS plaque, cord infarction

Localization of Sensory Deficits

Peripheral Nerve (Single Nerve / Mononeuropathy)

• Follows anatomic nerve territory
• Common: carpal tunnel (median nerve at wrist), ulnar at elbow, peroneal at fibular head
• Tinel's sign over nerve entrapment site

Polyneuropathy

• Stocking-glove pattern (length-dependent: longest fibers first)
• Usually begins distally, symmetrically
• Causes: diabetes (most common), alcohol, B12 deficiency, uremia, chemotherapy, hereditary (CMT)

Radiculopathy

• Dermatomal distribution
• Associated with neck or back pain, often exacerbated by Valsalva
• Key dermatomal levels:
  • C6: thumb and index finger
  • C7: middle finger, triceps
  • C8: ring and little finger
  • L4: medial foot/knee
  • L5: dorsum of foot, great toe
  • S1: lateral foot, heel, Achilles reflex

Spinal Cord

• Sensory level: all modalities affected below the lesion
• Dissociated sensory loss: pain/temperature but not proprioception/vibration (or vice versa)
• Syringomyelia: cape-like distribution of dissociated loss (pain/temperature in arms/upper chest), sparing proprioception

Brainstem

• Cranial nerve involvement + crossed sensory signs
• Lateral medullary syndrome (Wallenberg): ipsilateral face loss (pain/temp via trigeminal) + contralateral body loss (spinothalamic)

Thalamus

• Contralateral hemisensory loss (all modalities)
• Thalamic pain syndrome (Dejerine-Roussy): after thalamic infarct, severe burning pain on affected side

Cortex (Parietal Lobe)

• Contralateral sensory loss, especially discriminative sensation
• Two-point discrimination, stereognosis (identifying objects by touch), graphesthesia (identifying numbers written on skin)
• Loss of these = parietal cortex dysfunction

Small-Fiber vs Large-Fiber Neuropathy

Key Sensory Syndromes

• Carpal Tunnel Syndrome: median nerve compression at wrist; pain/tingling in thumb/index/middle finger, worse at night; Tinel's and Phalen's positive; EMG diagnostic; treatment: wrist splint, corticosteroid injection, surgical decompression
• Vitamin B12 Deficiency (subacute combined degeneration): dorsal column + corticospinal tract; vibration/proprioception loss + weakness + spasticity; megaloblastic anemia; check serum B12, methylmalonic acid
• Tabes Dorsalis (neurosyphilis): dorsal column destruction; Argyll Robertson pupils, lightning pains, Romberg positive, Charcot joints
• Diabetic Neuropathy: most common peripheral neuropathy worldwide; predominantly small fiber early (pain, burning, loss of temp/pain), progresses to large fiber (proprioception loss, areflexia)

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CHAPTER 28 - GAIT DISORDERS, IMBALANCE, AND FALLS

Overview

Classification of Gait Disorders

1. Hemiplegic Gait (UMN - Unilateral)

• Circumduction of affected leg (stiff, extended)
• Arm held flexed and adducted
• Cause: stroke, brain tumor, MS

2. Paraplegic/Scissors Gait (UMN - Bilateral)

• Stiff, slow, legs cross over each other
• Cause: spinal cord disease, bilateral cerebral lesions, MS, CP

3. Steppage Gait (Foot Drop - LMN)

• High stepping to clear the dragging foot
• Cause: peroneal nerve palsy, L5 radiculopathy, Charcot-Marie-Tooth, GBS

4. Cerebellar Ataxic Gait

• Wide-based, staggering, irregular stride length
• Cannot tandem walk
• Cause: cerebellar disease (alcohol, MS, paraneoplastic, hereditary ataxias, stroke)

5. Sensory Ataxic Gait

• Wide-based, high-stepping, visually dependent
• Romberg positive (falls when eyes closed)
• Cause: proprioception loss (polyneuropathy, dorsal column disease)

6. Parkinsonian Gait

• Shuffling, short steps, reduced arm swing, stooped posture
• Freezing at doorways, festination (accelerating to maintain balance)
• Difficulty initiating (start hesitation) and turning
• Cause: Parkinson's disease, DLB, PSP, MSA, drug-induced parkinsonism

7. Antalgic Gait

• Shortened stance phase on painful side
• Cause: arthritis, hip pathology, painful foot conditions

8. Cautious Gait

• Slow, wide-based, reduced step length but normal neurologic exam
• Fear of falling; often in elderly after a fall
• Responds to confidence-building/rehabilitation

9. Frontal Gait (Apraxia of Gait)

• "Magnetic" or "glued to floor" appearance
• Short shuffling steps, difficulty initiating, wide base
• Preserved limb function when lying down (unlike Parkinson's)
• Cause: normal pressure hydrocephalus (NPH), cerebrovascular disease, frontal lobe lesions

Assessment of the Patient with Gait Disorders

• Falls with eyes closed = positive Romberg = sensory ataxia (proprioception loss)
• Falls with eyes open and closed = cerebellar ataxia or severe vestibular disease

Falls

Risk Factors for Falls in Older Adults (Table 28-3)

• Muscle weakness, use of assistive devices, osteoarthritis
• Orthostatic hypotension
• Depression
• Cognitive impairment
• Vision impairment (cataracts, glaucoma, macular degeneration)
• Vestibular dysfunction
• Foot problems (hallux valgus, hammer toes, poor footwear)

• Polypharmacy
• Antipsychotics, antidepressants, benzodiazepines, anticholinergics, antihypertensives, diuretics, opioids, antiepileptics, antiarrhythmics

• Poor lighting, loose rugs, slippery floors, lack of grab bars

Red Flags Suggesting Serious Cause

• Drop without provocation: suspect syncope, seizure, neurologic event
• Gait freezing/festination: parkinsonism
• Falls after arising from chair: muscle weakness
• Falls in poor lighting or changing footing: somatosensory/visual/vestibular deficit

Physical Examination for Falls

1. Cardiac exam (rhythm irregularities, murmurs)
2. Orthostatic BP (supine, standing at 1 min and 3 min): systolic drop >20 mmHg, diastolic >10 mmHg, or marked HR increase is significant
3. Visual acuity (with patient's normal eyewear)
4. Postural assessment (kyphosis, scoliosis)
5. Foot inspection (calluses, hallux valgus, hammer toes, footwear fit)
6. Mental status
7. Lower extremity motor exam (hip flexors/abductors, knee extensors, ankle dorsiflexors)
8. Sensory exam (monofilament testing for neuropathy)
9. Functional mobility testing (TUG)

Interventions to Reduce Fall Risk

• Exercise programs (strength + balance): most effective single intervention
• Medication review and rationalization (especially benzodiazepines, antihypertensives)
• Home safety assessment and modification
• Orthostatic hypotension treatment
• Vision correction
• Assistive devices (cane, walker) - properly fitted
• Vitamin D supplementation (reduces falls and fractures in deficient elderly)
• Hip protectors: reduce fracture risk but compliance is poor

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CHAPTER 29 - CONFUSION AND DELIRIUM

Definitions

• Acute onset and fluctuating course (hallmark)
• Inattention (cardinal feature - inability to sustain, shift, focus attention)
• Disorganized thinking, disorientation
• Altered level of consciousness
• Perceptual disturbances (visual hallucinations most common)
• Sleep-wake cycle disruption
• Psychomotor changes

Subtypes

• Hyperactive delirium (25%): agitation, restlessness, combativeness, hallucinations - easier to recognize
• Hypoactive delirium (50%): withdrawn, quiet, reduced responsiveness - often missed, worse prognosis
• Mixed (25%)

Epidemiology

• Affects 15-50% of hospitalized patients >65 years
• ICU rates: 70-87%
• Postoperative: 10-52% (especially cardiac and orthopedic surgery)
• Associated with increased mortality, prolonged hospitalization, higher discharge to nursing home, accelerated cognitive decline

Pathophysiology

• Cholinergic deficiency (anticholinergic drugs are a major cause)
• Dopaminergic excess
• Neuroinflammation (IL-6, TNF-alpha elevation)
• Disruption of cortical-subcortical networks
• GABAergic dysfunction (alcohol withdrawal delirium)
• Disrupted thalamocortical connectivity reducing cortical integration

Clinical Features of Delirium

• Impaired attention (patient cannot recite months backwards or do serial 7s)
• Fluctuating consciousness (lucid at times, confused at others)
• Acute onset (hours to days)

• Disorientation (time first, then place, then person)
• Language impairment (incoherent speech)
• Memory impairment (cannot register new information)
• Visuospatial dysfunction
• Sleep disturbance (reversal of sleep-wake cycle)
• Perceptual disturbances: illusions > hallucinations (visual > auditory)
• Mood disturbances: fear, anxiety, paranoia

Differential Diagnosis (Table 29-1)

Diagnosis - Confusion Assessment Method (CAM)

1. Acute onset and fluctuating course
2. Inattention (inability to follow instructions or sustain attention)
3. Disorganized thinking
4. Altered level of consciousness

Workup

• Complete metabolic panel (electrolytes, glucose, BUN/creatinine, LFTs, calcium)
• CBC
• Urinalysis and urine culture
• Blood cultures if infection suspected
• Pulse oximetry, ABG if hypoxia/hypercapnia suspected
• ECG
• Thyroid function
• Vitamin B1, B12 levels
• Medication review (especially anticholinergics, sedatives)

• Focal neurologic signs
• History of fall/head trauma
• New-onset seizure
• Fever + meningismus (do CT first, then LP)
• No obvious medical cause found

Management

Non-pharmacologic (First-line, Evidence-Based)

• Reorientation: clocks, calendars, regular orientation by staff
• Sleep: avoid nighttime interruptions, reduce noise/light, avoid anticholinergics at night
• Early mobilization: get out of bed, walking when safe
• Sensory optimization: hearing aids, eyeglasses, good lighting
• Hydration and nutrition
• Avoid restraints (worsen delirium)
• Family presence and familiar voices

Pharmacologic (Symptom Management Only - NOT proven to reduce duration)

• Haloperidol 0.5-1 mg IV/IM/PO: first-line; avoid in Parkinson's/DLB
• Quetiapine 12.5-25 mg: preferred in Parkinson's/DLB; more sedating
• Olanzapine: alternative
• Avoid benzodiazepines (worsen most delirium) EXCEPT:
  • Alcohol/benzodiazepine withdrawal delirium: benzodiazepines are treatment
  • Seizure-related
• Dexmedetomidine (ICU): sedation that preserves arousability; reduces delirium duration vs. benzodiazepines

Prognosis

• Most cases resolve when underlying cause treated
• Elderly: cognitive function may not return fully to baseline; accelerates existing dementia
• Delirium superimposed on dementia: highest morbidity

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CHAPTER 30 - COMA

Consciousness - Two Components

1. Arousal/Wakefulness - maintained by the ascending reticular activating system (ARAS) in the brainstem reticular formation (midbrain/upper pons)
2. Awareness/Content - maintained by widespread cortical activity

Spectrum of Impaired Consciousness

Causes of Coma

Structural Causes (Focal Brainstem or Bilateral Hemisphere)

• Supratentorial mass (stroke, tumor, subdural hematoma): compresses/displaces brainstem via herniation
• Infratentorial lesion (cerebellar/brainstem stroke or hemorrhage): direct compression of ARAS
• Herniation syndromes:
  • Central (transtentorial): symmetric downward displacement; small pupils → midposition fixed → pontine (pinpoint)
  • Uncal: ipsilateral CN III palsy (dilated pupil) + contralateral hemiparesis → bilateral signs

Diffuse/Metabolic Causes

• Hypoglycemia (most reversible and most important to treat immediately)
• Hyperglycemia (hyperosmolar)
• Hypo/hypernatremia
• Hypoxia/hypercapnia
• Hepatic encephalopathy: ammonia accumulation, asterixis (flapping tremor), fetor hepaticus; serum ammonia
• Uremic encephalopathy: BUN elevation; asterixis, multifocal myoclonus
• Drug/toxin-induced coma (most common reversible cause): barbiturates, opioids (pinpoint pupils), benzodiazepines, alcohol
  • Atropinics: dilated pupils + tachycardia + dry skin
  • Opiates: pinpoint pupils <1 mm, respiratory depression
  • Barbiturates: can mimic brain death (exclude before declaring brain death)
• Epileptic coma: nonconvulsive status epilepticus (NCSE) → always consider, order EEG
• Postictal state: self-limited, diffuse EEG slowing, minutes to hours
• Hypothermia

Approach to the Comatose Patient

Immediate Priorities (ABC)

1. Airway, breathing, circulation
2. IV access, cardiac monitoring
3. Dextrose 50% if hypoglycemic (give thiamine first if Wernicke's possible: 100 mg IV thiamine before glucose)
4. Naloxone 0.4-2 mg IV if opioid overdose suspected (miosis, slow breathing)

History (from witnesses/family/EMS)

1. Circumstances and rapidity of onset
2. Antecedent symptoms (headache, fever, confusion, focal weakness, seizure, dizziness, vomiting)
3. Medications, drugs, alcohol, toxins
4. Chronic diseases (liver, kidney, lung, heart, diabetes)

Neurological Examination in Coma

• Equal and reactive: metabolic coma (most cases)
• Unequal: structural lesion; unilateral dilated fixed pupil = ipsilateral uncal herniation or CN III palsy
• Bilaterally fixed mid-position (4-5 mm): midbrain lesion
• Bilateral pinpoint: pontine hemorrhage OR opiate overdose
• Bilateral fixed and dilated: severe anoxia, atropinics, or brain death

• Doll's eye maneuver (oculocephalic reflex): head turned, eyes should move opposite = intact brainstem
• Caloric testing (oculovestibular reflex): 50 mL ice water in ear; tonic eye deviation toward cold ear if brainstem intact; absent in brainstem death
• Conjugate gaze deviation: toward lesion (hemispheric stroke - "eyes look at lesion") or away from lesion (pontine lesion)

• Purposeful withdrawal = cortex partially intact
• Decorticate posturing (arm flexion, leg extension): cortical/subcortical damage above midbrain
• Decerebrate posturing (arm + leg extension, internal rotation): midbrain/upper pons damage
• No response: structural or severe metabolic damage

• Cheyne-Stokes: bilateral cortical/diencephalic dysfunction or heart failure
• Central neurogenic hyperventilation: midbrain/pontine damage
• Ataxic (Biot's): pontomedullary; precedes respiratory arrest

Brain Death Criteria

1. Known irreversible cause (structural or metabolic)
2. Normothermia, normotension, no sedating drugs
3. Absence of all brainstem reflexes: pupils, corneal, oculocephalic, oculovestibular, gag, cough
4. Absent spontaneous respiration (apnea test: PCO2 rises >20 mmHg above baseline without respiratory effort)
5. Confirmatory tests (if clinical exam cannot be completed): EEG (isoelectric), cerebral angiography (no flow), nuclear scan, transcranial Doppler

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CHAPTER 31 - DEMENTIA

Definition

• 6 million affected in USA; >$300 billion annual health care cost

• Episodic memory (recall of events specific in time and place) is most commonly lost
• 10% of persons >70 years and 20-40% of individuals >85 years have clinically identifiable memory loss

Prodromal Stages

• Preclinical AD: brain pathology present, no symptoms (detected by amyloid PET/CSF)
• Mild Cognitive Impairment (MCI): cognitive decline that does NOT impair independence; 10-15% per year convert to dementia
• Dementia: cognitive decline sufficient to impair ADLs

Functional Anatomy

• Starts in entorhinal cortex → hippocampus + limbic structures → basal temporal areas → lateral/posterior temporal + parietal neocortex → widespread
• Presents with episodic memory loss, later aphasia, visuospatial deficits, executive dysfunction

• Dorsolateral prefrontal cortex / caudate: executive dysfunction, poor organization, impaired working memory
• Lateral orbital frontal / ventromedial caudate: impulsiveness, distractibility, disinhibition
• Anterior cingulate / medial striatum: apathy, abulia

Causes of Dementia

Most Common

1. Alzheimer's Disease (AD) - 60-70% of all dementia
2. Vascular Dementia (VaD) - 15-20%
3. Lewy Body Dementia (DLB) - 5-15%
4. Frontotemporal Dementia (FTD) - 5-10% (younger onset, <65)

Reversible/Treatable Causes (must always exclude)

• Hypothyroidism
• Vitamin B12 deficiency (subacute combined degeneration)
• Neurosyphilis
• Normal pressure hydrocephalus (NPH)
• Subdural hematoma (chronic)
• Depression (pseudodementia)
• Medication toxicity (anticholinergics, benzodiazepines)
• Wernicke-Korsakoff syndrome

Other Causes

• Prion diseases (CJD, fatal familial insomnia) - rapidly progressive
• Huntington's disease
• Paraneoplastic limbic encephalitis
• CNS vasculitis
• HIV dementia
• Chronic traumatic encephalopathy (CTE)
• Wilson's disease (young patients)

Clinical Features by Type

Alzheimer's Disease

• Insidious onset, gradual progression
• Episodic memory loss first (cannot form new memories, forgets appointments)
• Language: anomia (word-finding difficulty) early
• Visuospatial: gets lost driving, trouble with navigation
• Later: executive dysfunction, personality change, depression, delusions (paranoid)
• End-stage: cannot recognize family, incontinence, immobility, dysphagia
• Genetics: APOE ε4 (risk factor, not deterministic); Presenilin 1/2 mutations (autosomal dominant early-onset familial AD); APP mutations
• Pathology: amyloid plaques + neurofibrillary tangles (tau); amyloid burden correlates with stage

Vascular Dementia

• Step-wise deterioration vs. insidious (though can be gradual with small vessel disease)
• Risk factors: hypertension, diabetes, atrial fibrillation, smoking, hyperlipidemia
• Neuroimaging: white matter changes (leukoaraiosis), lacunar infarcts
• Executive dysfunction, slow processing speed, frontal features predominate over memory early
• Treatment: control vascular risk factors; aspirin; statins

Dementia with Lewy Bodies (DLB)

• Clinical triad: 1) Fluctuating cognition (hour-to-hour, day-to-day) 2) Vivid visual hallucinations (well-formed, often people/animals) 3) Parkinsonism (motor features within 1 year of dementia)
• REM sleep behavior disorder (RBD): acts out dreams, physically kicks/punches during sleep - often precedes DLB by years
• Extreme sensitivity to antipsychotics (haloperidol can cause severe deterioration or death)
• Treatment: rivastigmine (cholinesterase inhibitor); levodopa for parkinsonism (use cautiously); avoid typical antipsychotics; quetiapine if antipsychotic needed

Frontotemporal Dementia (FTD)

• Onset typically <65 years
• Behavioral variant (bvFTD): disinhibition, impulsivity, hyperphagia (overeating), compulsive behaviors, apathy, loss of empathy, social inappropriateness
• Memory often relatively PRESERVED early
• Primary progressive aphasia (PPA): language impairment as primary deficit
  • Semantic variant: loss of word meanings (can speak fluently but uses wrong words)
  • Non-fluent/agrammatic: effortful, halting speech
  • Logopenic: word-finding pauses, impaired repetition
• Pathology: TDP-43, FUS, or tau inclusions; genes: C9orf72, GRN, MAPT
• No approved treatments; symptomatic management

Approach to the Patient with Dementia

History

• Onset: acute (delirium, stroke, Wernicke's) vs. insidious (AD, FTD) vs. stepwise (vascular)
• Course: progressive (neurodegenerative) vs. fluctuating (DLB, vascular)
• Pattern: memory first (AD), behavior first (FTD), parkinsonism + cognition (DLB), language (PPA)
• Family history (AD, HD, FTD can be inherited)
• Medications (anticholinergics, benzodiazepines)
• Vascular risk factors
• Depression screening (PHQ-9)
• Alcohol and substance use

Physical and Neurological Examination

• Parkinsonism (DLB, PSP, MSA)
• Focal signs (vascular, structural)
• Gait (NPH: magnetic gait)
• Eye movements: supranuclear gaze palsy (PSP: cannot look down voluntarily)
• Reflexes: frontal release signs (grasp, snout, palmomental) in frontal disease
• Primitive reflexes: indicates frontal lobe pathology

Cognitive Examination

• MMSE (Mini-Mental State Examination): 30 points; <24 = likely dementia; 18-24 = mild; 10-17 = moderate; <10 = severe
• MoCA (Montreal Cognitive Assessment): 30 points; <26 = mild impairment; more sensitive for MCI than MMSE; tests executive function better
• Clock Drawing Test: sensitive for visuospatial and executive deficits

Laboratory Tests

• CBC, comprehensive metabolic panel
• TSH (hypothyroidism)
• Vitamin B12 level
• Syphilis serology (RPR/VDRL, FTA-ABS)
• HIV testing (in at-risk populations)
• Folate (if B12 normal but deficiency suspected)

• Normal pressure hydrocephalus: LP with large-volume tap (30-50 mL); improvement in gait after tap = diagnostic and predicts surgical response to shunt
• Alzheimer's: CSF amyloid-beta 42 (decreased), tau (increased), phospho-tau (increased) - now standard biomarkers for AD diagnosis
• CJD: 14-3-3 protein, RT-QuIC assay (high sensitivity/specificity)

• MRI brain: preferred over CT; shows hippocampal/medial temporal atrophy (AD), white matter changes (vascular), frontotemporal atrophy (FTD), midbrain atrophy "hummingbird sign" (PSP)
• FDG-PET: hypometabolism; AD = temporoparietal, posterior cingulate; FTD = frontal/temporal
• Amyloid PET (florbetapir, florbetaben): now FDA-approved for detecting amyloid deposition; negative = excludes AD
• DaT scan (dopamine transporter SPECT): reduced striatal uptake in DLB and Parkinson's; normal in AD

Global Considerations

Treatment

• Lecanemab (Leqembi): FDA-approved 2023 for early AD (MCI/mild AD with confirmed amyloid); monoclonal antibody targeting amyloid-beta protofibrils; slows cognitive decline by ~27% at 18 months; risk of ARIA (amyloid-related imaging abnormalities - brain edema/microhemorrhages)
• Donanemab: approved 2024; similar class; higher amyloid clearance

• Depression: SSRIs (sertraline, escitalopram preferred over TCAs)
• Agitation/psychosis: non-pharmacologic first; if needed, quetiapine or risperidone (low dose); AVOID haloperidol in DLB
• Sleep disturbance: melatonin, low-dose trazodone; avoid benzodiazepines
• Caregiver education and support are as important as drug therapy

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CHAPTER 33 - SLEEP DISORDERS

Physiology of Circadian Rhythmicity

Sleep Architecture

• Stage N1 (light): 5%; transition from wake; slow eye movements
• Stage N2: 45%; K complexes, sleep spindles; bulk of sleep
• Stage N3 (slow-wave, deep): 25%; delta waves; growth hormone released; most restorative

• NREM (slow-wave) sleep: sleepwalking, night terrors, enuresis (sleep drunkenness)
• REM sleep: REM sleep behavior disorder (RBD) - acts out dreams

Sleep Disorders Overview

INSOMNIA

• Primary (Chronic Insomnia Disorder): no identifiable medical/psychiatric cause
• Secondary: due to pain, depression, anxiety, medical illness, drugs

• Sleep history: onset, duration, sleep schedule, daytime function, napping
• Sleep diary (2 weeks): bedtime, wake time, naps, estimated total sleep time
• Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI)
• Polysomnography (PSG): NOT routinely indicated for insomnia; use if sleep apnea or parasomnia suspected
• Actigraphy: wrist-based movement monitoring; useful for circadian disorders

1. Sleep restriction therapy: limit time in bed to actual sleep time → builds homeostatic drive
2. Stimulus control: bed only for sleep and sex; no screens/reading in bed; get up if cannot sleep after 20 min
3. Sleep hygiene: consistent schedule, avoid caffeine after noon, dark/cool room, no alcohol close to bedtime
4. Relaxation techniques: progressive muscle relaxation, mindfulness
5. Cognitive restructuring: address catastrophic thoughts about sleep

NARCOLEPSY

1. Excessive daytime sleepiness (EDS) - the cardinal feature; sudden irresistible sleep attacks
2. Cataplexy (specific to Type 1 narcolepsy): sudden bilateral loss of muscle tone triggered by strong emotion (laughter, surprise, anger); consciousness preserved; lasts seconds to minutes; pathognomonic for narcolepsy
3. Sleep paralysis: transient inability to move at sleep onset or awakening; lasts seconds to minutes; common but not specific
4. Hypnagogic/hypnopompic hallucinations: vivid dream-like hallucinations at sleep onset/awakening
5. Disrupted nocturnal sleep: paradoxically, night sleep is fragmented

• Type 1 Narcolepsy (with cataplexy): CSF hypocretin-1 <110 pg/mL (definitive); HLA-DQB1*06:02 positive in 95%
• Type 2 Narcolepsy (without cataplexy): normal/borderline hypocretin; less specific

• MSLT (Multiple Sleep Latency Test): mean sleep onset latency ≤8 minutes + ≥2 sleep-onset REM periods (SOREMPs) in 5 nap opportunities; most important diagnostic test
• PSG first night (to rule out sleep apnea and show sleep-onset REM)
• CSF hypocretin level (if cataplexy present and definitive diagnosis needed)

SLEEP APNEA

• Repetitive upper airway collapse during sleep → apnea (≥10 sec) → arousal → fragmented sleep
• Symptoms: loud snoring, witnessed apneas, excessive daytime sleepiness, morning headaches, nocturia, cognitive impairment, irritability, depression
• Risk factors: obesity (BMI >30), male sex, age, large neck circumference (>40 cm women, >43 cm men), craniofacial abnormalities, hypothyroidism, acromegaly, alcohol/sedatives
• Screening: STOP-BANG questionnaire (Snoring, Tired, Observed apnea, blood Pressure, BMI >35, Age >50, Neck circumference, Gender male)
• Diagnosis: Polysomnography (PSG) gold standard; AHI (Apnea-Hypopnea Index) ≥5/hr = OSA; ≥15/hr = moderate; ≥30/hr = severe. Home sleep testing acceptable for uncomplicated suspected OSA.
• Complications: hypertension (OSA is most common cause of secondary HTN), type 2 diabetes, atrial fibrillation (AF), right heart failure (cor pulmonale), pulmonary hypertension, increased stroke and MI risk
• Treatment:
  • CPAP (Continuous Positive Airway Pressure): first-line for all severity; pneumatic splint for airway
  • Positional therapy: if AHI significantly worse in supine position
  • Weight loss: can cure mild OSA; adjunct in moderate-severe
  • Mandibular advancement device (MAD): for mild-moderate OSA; alternative to CPAP in CPAP-intolerant
  • Surgery (UPPP): for specific craniofacial anatomy; less effective than CPAP
  • Hypoglossal nerve stimulator (Inspire): implanted device for CPAP-intolerant moderate-severe OSA; activates tongue protrusion

• Absence of respiratory effort (no airway obstruction; brainstem fails to send respiratory drive)
• Causes: heart failure (Cheyne-Stokes breathing pattern), stroke/brainstem lesion, opioid-induced, high altitude
• Treatment: treat underlying cause; ASV (adaptive servo-ventilation) for CHF-associated CSA

CIRCADIAN RHYTHM SLEEP DISORDERS

PARASOMNIAS

• Occur in slow-wave sleep (N3), first third of night
• Incomplete arousal from deep sleep
• Sleepwalking (Somnambulism): ambulation during sleep; eyes open but not aware; common in children; usually resolve with age; avoid sleep deprivation (trigger); safety measures
• Night Terrors (Sleep Terrors): intense screaming/terror, autonomic arousal (HR, sweating), no memory of event; common in children; reassurance; different from nightmares (which are REM phenomena)
• Confusional Arousals: incomplete awakening, confused behavior
• Triggers: sleep deprivation, febrile illness, alcohol, sedatives, stress
• Treatment: sleep hygiene, safety measures; clonazepam or trazodone for adults with injury risk

• Loss of normal REM atonia → acting out dreams; punching, kicking, yelling
• Dream content is usually aggressive/threatening
• Partner injuries are common
• Strongly associated with alpha-synuclein neurodegenerative diseases: Parkinson's disease, DLB, MSA - RBD often precedes motor symptoms by 10-15 years (prodromal marker)
• Diagnosis: PSG showing REM without atonia
• Treatment: Clonazepam 0.5-2 mg at bedtime (first-line); melatonin 3-12 mg (safer in elderly/cognitive impairment); bed safety measures (pad floors, remove sharp objects, separate beds)

• Recurrent disturbing dreams with full awakening and recall
• Common in PTSD
• Treatment: image rehearsal therapy (CBT-based), prazosin (especially in PTSD-related nightmares - reduces noradrenergic activity)

RESTLESS LEGS SYNDROME (RLS) / WILLIS-EKBOM DISEASE

1. Urge to move legs, usually with uncomfortable sensations
2. Symptoms worsen at rest/inactivity
3. Partially/completely relieved by movement
4. Worse in evening/night (circadian component)

• Iron supplementation if ferritin <75 µg/L: oral ferrous sulfate with vitamin C; IV iron if malabsorption or refractory
• Dopamine agonists: pramipexole, ropinirole, rotigotine patch (FDA-approved; first-line pharmacotherapy)
  • Risk of augmentation: worsening of symptoms, earlier onset, spread to arms/trunk (common with long-term use; highest with levodopa)
• Alpha-2-delta calcium channel ligands (gabapentin enacarbil, pregabalin): preferred if pain component, augmentation, or neuropathy co-exists; now considered first-line by many guidelines
• Opioids (oxycodone, methadone): for refractory severe cases
• Benzodiazepines: sleep maintenance when other treatments fail

• Repetitive limb movements during NREM sleep (0.5-5 sec each, every 20-40 sec)
• Not the same as RLS (awake vs. asleep)
• Diagnosed on PSG; PLMI (PLM index) ≥15/hr
• Only treat if causing sleep disruption; same medications as RLS

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KEY CLINICAL SYNTHESIS - HIGH-YIELD EXAM PEARLS

Localization Quick Reference

Drugs That Worsen Key Conditions

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HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 22E (2025)

Section 4: Disorders of Eyes, Ears, Nose, and Throat

Complete Clinical Notes — Chapters 34 through 38

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CHAPTER 34 - DISORDERS OF THE EYE

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THE HUMAN VISUAL SYSTEM

• 100 million rods: scotopic (dim light) vision; no color discrimination
• 5 million cones: photopic (daylight) vision; color and high spatial resolution; concentrated in the macula (central 10° of vision)
• Fovea: a small pit in the center of the macula, packed exclusively with cones; provides the sharpest visual acuity
• Ganglion cells: 1 million per retina; 1 million fibers per optic nerve; translate retinal images into action potentials
• Melanopsin ganglion cells: intrinsically photosensitive; govern pupillary constriction and circadian rhythms via projections to pretectal olivary nuclei (pupil) and SCN (circadian)

• Nasal fibers (from temporal visual fields) decussate at the chiasm
• Temporal fibers (from nasal visual fields) remain ipsilateral
• Lesion at chiasm → bitemporal hemianopia (classic pituitary adenoma pattern)

• CN III (oculomotor): superior, inferior, and medial rectus; inferior oblique; levator palpebrae; pupil constriction (parasympathetics via ciliary ganglion)
• CN IV (trochlear): superior oblique (intorts and depresses eye)
• CN VI (abducens): lateral rectus

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CLINICAL ASSESSMENT OF VISUAL FUNCTION

Refractive State

• Emmetropia: no refractive error; parallel rays focus on retina
• Myopia (nearsightedness): eyeball too long; image focuses in front of retina; corrected with concave (minus) lens
• Hyperopia (farsightedness): eyeball too short; image focuses behind retina; corrected with convex (plus) lens
• Astigmatism: uneven corneal curvature; two focal points; corrected with cylindrical lens
• Presbyopia: age-related loss of accommodative power (lens stiffness); begins ~40-45 years; corrected with reading glasses

Visual Acuity

• Tested with Snellen chart at 20 feet (6 meters)
• 20/20: normal; can read letters that a normal eye reads at 20 feet
• 20/200: legal blindness in USA
• Always test each eye separately with patient's corrective lenses
• Pinhole test: improves visual acuity if blurring is refractive in origin (pinhole eliminates peripheral, unfocused rays). If pinhole DOES NOT improve vision → media opacity (cataract) or retinal/neurologic disease

Pupils

• Swinging flashlight test: light swung from normal eye to affected eye → BOTH pupils dilate (paradoxical dilation)
• Indicates unilateral optic nerve or severe retinal disease
• Present in: optic neuritis, optic nerve compression, severe retinal detachment
• NOT present in media opacities (cataract) or cortical lesions

• Miosis (small pupil), ptosis (partial), anhidrosis (depending on level)
• Caused by disruption of the sympathetic chain at any level: central (hypothalamus → C8-T2 cord), preganglionic (T1 → superior cervical ganglion; lung apex/Pancoast tumor, carotid artery dissection), postganglionic (carotid siphon to orbit)
• Cocaine test: fails to dilate Horner's pupil (no norepinephrine release); confirms Horner's
• Hydroxyamphetamine test: dilates postganglionic but not 3rd-order Horner's (differentiates level)
• Acute painful Horner's + ipsilateral neck pain → carotid artery dissection until proven otherwise → urgent vascular imaging

• "Down and out" gaze, ptosis, dilated non-reactive pupil
• If pupil involved: compressive etiology (posterior communicating artery aneurysm, uncal herniation) - EMERGENCY
• If pupil spared (often): microvascular infarct (diabetes, hypertension) - benign
• RULE: Pupil-involving CN III palsy = ruptured/expanding PCA aneurysm until proven otherwise → immediate neuroimaging

Eye Movements and Alignment

• Esotropia: eye turns inward
• Exotropia: eye turns outward
• Hypertropia: eye turns upward
• Detected by the cover test and cover-uncover test

Color Vision

• Color blindness: mostly X-linked (red-green; 8% of males, 0.5% females); tested with Ishihara plates
• Acquired dyschromatopsia (particularly red-green impairment): often first sign of optic nerve disease (optic neuritis). A patient may notice that red appears "washed out" before any acuity change.

Visual Fields

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DISORDERS: RED OR PAINFUL EYE

Causes of Red Eye - Diagnostic Approach

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TRANSIENT OR SUDDEN VISUAL LOSS

Amaurosis Fugax (Transient Monocular Blindness)

• Sudden, painless, complete or partial monocular visual loss lasting seconds to minutes, "like a curtain descending"
• Caused by emboli (platelet-fibrin from ipsilateral carotid artery; cholesterol - Hollenhorst plaques; cardiac sources)
• Represents a TIA of the eye (ophthalmic artery territory)
• Work-up: carotid duplex ultrasound, cardiac echo, ECG, CBC, ESR (rule out GCA), coagulation studies
• Treatment: antiplatelet therapy (aspirin); carotid endarterectomy if significant stenosis (>50-70%); anticoagulation if cardioembolic
• In patients >50 years, ALWAYS check ESR/CRP to rule out giant cell arteritis

Giant Cell Arteritis (Temporal Arteritis) - VISION EMERGENCY

• Granulomatous vasculitis of medium/large vessels; exclusively in patients >50 years (mean 70 years)
• Symptoms: headache (temporal/occipital), scalp tenderness, jaw claudication (pathognomonic), visual loss, shoulder/hip girdle aches (polymyalgia rheumatica in 50%), fever, weight loss
• Visual loss: anterior ischemic optic neuropathy (AION) - altitudinal field defect, pale swollen optic disc; can also cause posterior ischemic optic neuropathy or central retinal artery occlusion; bilateral involvement in 25-50% without treatment
• Labs: ESR typically >50 mm/hr, often >100; CRP elevated; thrombocytosis
• Diagnosis: temporal artery biopsy (gold standard; 5 cm of vessel; skip lesions can give false negative - bilateral biopsy increases yield)
• Treatment: Start high-dose prednisolone (60-80 mg/day PO, or IV methylprednisolone if visual loss) IMMEDIATELY - DO NOT WAIT for biopsy results. Biopsy positive for 2 weeks after starting steroids.
• Tocilizumab (IL-6 inhibitor): approved as steroid-sparing agent for GCA

Anterior Ischemic Optic Neuropathy (AION)

• Arteritic AION (due to GCA): see above; devastating; emergency
• Non-arteritic AION (NAION): most common acute optic neuropathy in adults >50 years
  • Risk factors: small "disc at risk" (small cup-to-disc ratio), hypertension, diabetes, hyperlipidemia, sleep apnea
  • Sudden, painless, altitudinal (usually inferior) visual field loss; swollen optic disc
  • No proven treatment; control vascular risk factors
  • Recurrence in fellow eye: 15-20% risk over 5 years

Optic Neuritis

• Most common in young women (20-45 years); strongly associated with multiple sclerosis
• Subacute monocular visual loss (hours to days) + periocular pain worse with eye movement + red-green dyschromatopsia (often disproportionate to acuity loss) + APD
• Examination: optic disc swollen if anterior (papillitis) or normal if retrobulbar (70% of cases = "doctor sees nothing, patient sees nothing")
• Uhthoff's phenomenon: worsening with heat or exercise (pathognomonic of demyelination)
• MRI brain/orbits with gadolinium: essential; gadolinium enhancement of optic nerve confirms active demyelination; white matter lesions predict MS risk
• Treatment: IV methylprednisolone 1 g/day × 3 days speeds recovery (does not affect final visual outcome); interferon beta or other DMTs reduce risk of conversion to MS
• The Optic Neuritis Treatment Trial (ONTT): landmark study showing high-dose IV steroids speed recovery but oral prednisone alone increases relapse risk

Central Retinal Artery Occlusion (CRAO)

• Sudden, painless, complete monocular blindness; "cherry-red spot" on fundus (foveal choroidal perfusion persists while surrounding pale, edematous retina is ischemic)
• Embolic (most common), thrombotic, GCA
• Ophthalmic emergency: retinal ischemia tolerance is 90-100 minutes (shorter than brain)
• Management: ocular massage (dislodge embolus), anterior chamber paracentesis, lower IOP, pure oxygen (100%) - all have limited evidence; IV tPA within 4.5 hours (experimental); urgent cardiac and carotid evaluation; GCA must be excluded in older patients

Central Retinal Vein Occlusion (CRVO)

• "Blood and thunder" fundus: scattered flame hemorrhages in all four quadrants, disc edema, engorged veins
• Causes: hypertension, diabetes, glaucoma, hypercoagulable states
• Visual loss varies from mild to severe
• Complication: neovascular glaucoma (20%) at 3 months - "90-day glaucoma"; pan-retinal photocoagulation prophylaxis
• Treatment: anti-VEGF injections (ranibizumab, bevacizumab, aflibercept) for macular edema

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CHRONIC VISUAL LOSS

Age-Related Macular Degeneration (AMD)

• Most common cause of irreversible central vision loss in patients >55 years in developed countries

• Drusen deposits (yellow-white deposits between RPE and Bruch's membrane) + Geographic atrophy of RPE
• Gradual central vision loss; color vision affected; peripheral vision preserved
• No proven medical treatment for geographic atrophy; AREDS2 supplements (vitamins C, E, zinc, copper, lutein, zeaxanthin) reduce progression by 25% in intermediate AMD

• Choroidal neovascularization (CNV) - abnormal vessels grow under the retina, leak, bleed
• Metamorphopsia (distortion of straight lines - use Amsler grid for monitoring) + rapid central visual loss
• Treatment: Anti-VEGF injections (ranibizumab [Lucentis], bevacizumab [Avastin], aflibercept [Eylea]) - revolutionary; must be given early and repeatedly (monthly-bimonthly); can stabilize and sometimes improve vision

Diabetic Retinopathy

• Most common cause of new blindness in working-age adults (20-65 years) in developed countries
• Affects virtually 100% of Type 1 diabetics after 20 years; 60% of Type 2 diabetics after 20 years

• Non-proliferative DR (NPDR): microaneurysms (first sign), dot/blot hemorrhages, hard exudates (lipoproteins), cotton-wool spots (nerve fiber infarcts), venous beading, IRMA
• Proliferative DR (PDR): neovascularization at disc (NVD) or elsewhere (NVE) - high risk of vitreous hemorrhage and tractional retinal detachment; treat with pan-retinal photocoagulation (PRP) or anti-VEGF
• Diabetic Macular Edema (DME): can occur at any stage; central vision loss; treat with anti-VEGF (first-line) or intravitreal steroids

• Type 1 DM: ophthalmology exam at 5 years, then annually
• Type 2 DM: exam at diagnosis, then annually
• Optimal glycemic control (HbA1c <7%) and blood pressure control are paramount
• PRP for PDR; anti-VEGF for DME

Glaucoma

• Chronic optic neuropathy with characteristic cupping of the optic disc and visual field loss; often but NOT always associated with elevated IOP

• Most common form; slowly progressive; peripheral field loss first (arcuate scotoma) → tunnel vision → blindness
• Often asymptomatic until late (no pain, no red eye, no vision change until advanced)
• Risk factors: elevated IOP (>21 mmHg), family history (first-degree relative: 10× risk), African descent (higher prevalence and earlier onset), advanced age, myopia, thin central corneal thickness
• Diagnosis: optic disc assessment (cup-to-disc ratio >0.6, asymmetry >0.2, rim notching, disc hemorrhages), visual field testing (automated perimetry), IOP measurement, gonioscopy (open angle), OCT (retinal nerve fiber layer thickness - most sensitive early marker)
• Treatment: lower IOP (goal: 20-30% reduction)
  • Topical prostaglandin analogs (latanoprost, bimatoprost): first-line; once daily; most effective; side effects: iris pigmentation, eyelash growth
  • Beta-blockers (timolol): twice daily; contraindicated in asthma, COPD, bradycardia
  • Alpha-2 agonists (brimonidine): second-line
  • Carbonic anhydrase inhibitors (dorzolamide topical; acetazolamide oral)
  • Laser trabeculoplasty (SLT): effective, repeatable, laser applied to trabecular meshwork
  • Surgery (trabeculectomy, tube shunts): for medically refractory glaucoma

• Sudden, severe IOP rise (>50-80 mmHg) from pupillary block
• Severe eye pain, headache, nausea/vomiting, halos around lights, mid-dilated fixed pupil, rock-hard eye
• EMERGENCY - can cause permanent vision loss within hours
• Precipitants: dim light (dilates pupil, narrows angle), anticholinergics, antidepressants, decongestants
• Treatment: IV acetazolamide + topical timolol + pilocarpine (constricts pupil, pulls iris off angle) + mannitol IV; then laser peripheral iridotomy (PI) as definitive treatment
• Prophylactic PI to fellow eye (bilateral risk)

Cataract

• Opacification of the crystalline lens - most common cause of reversible blindness worldwide
• Types: nuclear (central, yellowish - commonest age-related), cortical (spoke-like opacities), posterior subcapsular (dense; associated with steroids and diabetes; disproportionate effect on reading vision in bright light)
• Symptoms: blurred vision, glare, halos, monocular diplopia, reduced contrast, color desaturation
• Treatment: surgical removal (phacoemulsification + intraocular lens [IOL] implant) - the most commonly performed surgery in the world; safe, effective, corrects refractive error
• Complications of surgery: posterior capsule opacification ("after-cataract") - treat with Nd:YAG laser capsulotomy

Retinal Detachment

• Separation of the neurosensory retina from the retinal pigment epithelium (RPE)
• Types:
  • Rhegmatogenous (most common): a tear/break in the retina allows vitreous fluid to seep under the retina
  • Tractional: fibrovascular tissue pulls retina off (diabetic PDR)
  • Exudative: fluid accumulates under retina without a break (tumor, uveitis)
• Symptoms: photopsia (flashes - vitreous traction), floaters (vitreous hemorrhage or pigment cells = "tobacco dust"), then a curtain or shadow in the peripheral visual field progressing centrally
• Macula-off detachment: central vision lost; requires urgent but not emergent surgery; macula-on: ophthalmologic emergency (same day/next day surgery to prevent macular detachment)
• Treatment: pneumatic retinopexy, scleral buckle, or vitrectomy

Retinitis Pigmentosa (RP)

• Hereditary retinal degeneration; primarily rods affected early (peripheral, night vision)
• Presents: night blindness (nyctalopia) in childhood/teens → progressive tunnel vision (concentric field loss) → eventual loss of central vision
• Fundus: bone spicule pigmentation, attenuated arterioles, waxy pallor of optic disc
• Electroretinogram (ERG): diagnostic; absent or markedly reduced scotopic (rod) responses
• No curative treatment; vitamin A palmitate supplementation (15,000 IU/day) may slow progression in adults (evidence limited)
• Important associations: Usher syndrome (RP + congenital sensorineural hearing loss); Laurence-Moon-Bardet-Biedl syndrome

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PROPTOSIS (EXOPHTHALMOS)

• Thyroid eye disease (Graves' orbitopathy): most common cause of unilateral and bilateral proptosis in adults; also causes lid retraction (Dalrymple's sign), lid lag (von Graefe's sign), chemosis, conjunctival injection; CT/MRI: enlarged extraocular muscles (spindle-shaped); can cause exposure keratopathy (corneal damage) and compressive optic neuropathy (emergency)
• Orbital cellulitis: post-sinusitis (typically ethmoid sinusitis in children); proptosis + lid swelling + pain + fever; needs urgent IV antibiotics and CT scan; risk of cavernous sinus thrombosis
• Orbital pseudotumor (idiopathic orbital inflammation): painful proptosis, responds dramatically to systemic corticosteroids
• Orbital tumors: capillary hemangioma (children), cavernous hemangioma (adults), lymphoma, metastases
• Carotid-cavernous fistula: pulsatile proptosis with bruit; dilated episcleral vessels; treat with endovascular embolization

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PTOSIS

• Aponeurotic ptosis (most common): dehiscence or disinserction of the levator aponeurosis; acquired (surgery, aging, contact lens wear); normal levator function, high skin crease
• Myogenic ptosis: muscular dystrophies, mitochondrial myopathy (CPEO), MG
• Neurogenic ptosis:
  • CN III palsy: ptosis + external ophthalmoplegia + dilated pupil (if compressive) or spared pupil (microvascular)
  • Horner's syndrome: partial ptosis (2-3 mm) + miosis + anhidrosis; sympathetic pathway disruption
  • MG: fatigable ptosis (worse with sustained upgaze - Cogan's lid twitch)
• Mechanical ptosis: from lid tumors, infiltration, edema

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DOUBLE VISION (DIPLOPIA)

• Superior oblique weakness → vertical diplopia, worse looking down (e.g., reading, descending stairs)
• Patients tilt head away from affected eye (to compensate - Parks-Bielschowsky three-step test)
• Causes: trauma (most common), congenital, microvascular infarct

• Lateral rectus weakness → horizontal diplopia, worse looking toward affected side; esotropia
• Can be a false localizing sign: raised ICP stretches CN VI over the petrous tip (does not indicate a pontine lesion)
• Causes: microvascular, raised ICP, trauma, cavernous sinus/orbital lesion; Gradenigo's syndrome (petrous apex: CN VI palsy + CN V, facial pain + chronic otitis media)

• Lesion of the medial longitudinal fasciculus (MLF) in the pons
• Results in: impaired adduction of ipsilateral eye (looking toward the side of the lesion) + nystagmus in contralateral abducting eye
• "Bilateral INO in a young woman" = multiple sclerosis (until proven otherwise)
• Unilateral INO in an older patient = pontine infarction

• Lesion at the level of the superior colliculi (pineal region tumor, hydrocephalus, MS)
• Triad: upward gaze palsy + convergence-retraction nystagmus + light-near dissociation
• Collier's sign: bilateral upper eyelid retraction ("setting sun" sign)

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CHAPTER 35 - DISORDERS OF SMELL AND TASTE

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ANATOMY AND PHYSIOLOGY

Olfaction

Gustation (Taste)

• CN VII (chorda tympani): anterior 2/3 of tongue
• CN IX (glossopharyngeal): posterior 1/3 of tongue
• CN X (vagus): epiglottis, larynx, esophagus

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DISORDERS OF OLFACTION

Classification

• Hyposmia: reduced sense of smell
• Anosmia: complete absence of smell
• Dysosmia/Parosmia: distorted smell perception (real odors perceived as different, often unpleasant)
• Phantosmia: smell hallucinations without an external stimulus
• Hyperosmia: heightened sensitivity to odors (migraine, pregnancy)

Causes of Olfactory Loss

1. Upper respiratory tract infection (URTI)/Post-viral - most common overall cause; typically hyposmia/anosmia after viral illness; COVID-19 caused mass anosmia globally
2. Nasal and sinus disease - nasal polyps, chronic rhinosinusitis, allergic rhinitis (conductive anosmia - mucus/swelling blocks odorants from reaching olfactory epithelium)
3. Head trauma - cribriform plate fracture or shear injury to olfactory filaments; anosmia in 5% of closed head injuries (worse prognosis for recovery than post-viral)
4. Aging - presbyosmia; affects >50% of adults >65 years; >75% of adults >80 years; significant contributor to poor appetite in elderly

• Parkinson's disease: anosmia is an early pre-motor feature (precedes tremor by years); bilateral; useful screening marker
• Alzheimer's disease: olfactory loss is early; correlates with entorhinal involvement
• Frontal lobe tumors (olfactory groove meningioma): compress olfactory bulbs/tracts; Foster Kennedy syndrome: ipsilateral anosmia + ipsilateral optic atrophy + contralateral papilledema
• Kallmann syndrome: congenital anosmia + hypogonadotropic hypogonadism (failure of GnRH neurons to migrate from olfactory placode to hypothalamus)
• Temporal lobe epilepsy: olfactory auras (uncinate fits) - typically unpleasant smell before a seizure
• COVID-19: direct infection of sustentacular cells in olfactory epithelium; often sudden onset anosmia as an early/isolated symptom; most recover within weeks-months; ~10% develop parosmia; mechanism distinct from blocking mucosa

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DISORDERS OF TASTE

Classification

• Hypogeusia/Ageusia: reduced/absent taste
• Dysgeusia: distorted taste; perceived as unpleasant/metallic
• Phantogeusia: taste hallucinations

Causes of Taste Disorders

• Dental disease, poor oral hygiene
• Xerostomia (dry mouth) - saliva is essential for taste (dissolves taste molecules)
• Oral infections (candidiasis, HSV)
• Radiation therapy to head/neck (damages taste buds and salivary glands)
• Burns to tongue (hot food/liquids)

• Bell's palsy (CN VII injury): loss of taste anterior 2/3 tongue on affected side + chorda tympani involvement
• Chorda tympani damage during middle ear surgery
• CN IX lesion
• Brainstem lesion (NTS involvement)
• Multiple sclerosis

• Zinc deficiency (hypogeusia, often with hyposmia): most treatable cause; supplement zinc
• Vitamin B12 and B3 (niacin) deficiency
• Hypothyroidism, diabetes
• Medications: metronidazole, clarithromycin, captopril (ACE inhibitors - metallic/bitter taste), lithium, carbamazepine, levodopa, penicillamine, propylthiouracil
• Renal failure, liver disease
• Cancer chemotherapy (cisplatin)

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CLINICAL EVALUATION OF SMELL AND TASTE

• UPSIT (University of Pennsylvania Smell Identification Test): 40-item "scratch and sniff" test; normative values by age/sex; most widely used clinical test; scores < appropriate age/sex percentile = hyposmia/anosmia
• Brief Smell Identification Test (B-SIT): 12-item screening version
• Sniffin' Sticks (European): tests threshold, discrimination, and identification (TDI score)
• Unilateral testing important for localization

• Electrogustometry (electrical stimulation)
• Chemical strip tests (paper with taste solutions)
• Whole-mouth versus regional testing

• MRI (including olfactory bulbs): gold standard for structural causes; assess olfactory bulb volume (reduced in most anosmias)
• CT sinuses: polyps, chronic sinusitis
• Labs: TSH, B12, zinc, RPR (syphilis), CBC
• Nasal endoscopy

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TREATMENT AND MANAGEMENT

Olfactory Loss

• Address underlying cause: treat sinusitis (topical/oral corticosteroids; surgery for polyps), stop offending medications, correct nutritional deficiencies
• Olfactory training: Sniffing 4 different odors (rose, eucalyptus, lemon, cloves) twice daily for ≥12 weeks; best evidence for post-infectious anosmia; neuroplasticity-based recovery; multiple studies show benefit
• Systemic corticosteroids: short course may benefit inflammatory causes; not for long-term use
• Zinc and vitamin A have been used but evidence limited
• Spontaneous recovery: best for post-viral (50-60% recover) and post-traumatic (30-40%); worst with aging
• Parosmia: often indicates partial nerve regeneration (actually a good prognostic sign); omega-3 fatty acids may help (small studies)

Taste Disorders

• Treat underlying cause
• Zinc supplementation for zinc deficiency (zinc sulfate 220 mg twice daily)
• Oral hygiene optimization
• Salivary substitutes for xerostomia
• Stopping offending medication often resolves drug-induced dysgeusia

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CHAPTER 36 - DISORDERS OF HEARING

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PHYSIOLOGY OF HEARING

• Basilar membrane: tonotopic organization - high frequencies basally (near oval window), low frequencies apically (at helicotrema)
• Inner hair cells (~3,500): primary auditory transducers; 90-95% of afferent innervation
• Outer hair cells (~20,000): cochlear amplifier; prestin-driven electromotility; responsible for exquisite frequency selectivity and sensitivity; receive efferent innervation
• Tip links between stereocilia: when displaced by basilar membrane movement, stretch to open mechanically gated K+/Ca2+ channels → depolarization → neurotransmitter (glutamate) release at base of inner hair cells → auditory nerve activation

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CLASSIFICATION OF HEARING LOSS

Conductive Hearing Loss (CHL)

• Cerumen impaction (most common cause): wax blocks canal
• Otitis media (acute and with effusion): middle ear fluid blocks ossicular motion
• Tympanic membrane perforation: trauma, chronic otitis media
• Otosclerosis: fixation of stapes footplate by abnormal bony remodeling; most common cause of progressive CHL in adults 20-45 years; autosomal dominant; Schwartze sign: reddish-orange tinge through tympanic membrane (flamingo pink blush = active otosclerosis); treatment: stapedectomy (surgical replacement of stapes with prosthesis) or sodium fluoride (slows progression)
• Ossicular discontinuity: trauma, chronic otitis media erosion of incus
• Cholesteatoma: keratinizing squamous epithelium in middle ear; can erode ossicles, mastoid, facial nerve canal, lateral semicircular canal; CT diagnosis; treatment: surgical excision

Sensorineural Hearing Loss (SNHL)

• Genetic (70% of congenital SNHL):
  • GJB2 (Connexin 26) mutations: most common cause; autosomal recessive; impairs K+ recycling in cochlea; responsible for ~50% of autosomal recessive SNHL
  • Pendred syndrome (SLC26A4): SNHL + goiter (thyroid enlargement) + enlarged vestibular aqueduct
  • Waardenburg syndrome: SNHL + white forelock + heterochromia iridis + dystopia canthorum (autosomal dominant; PAX3 mutation)
  • Usher syndrome: SNHL + retinitis pigmentosa (autosomal recessive)
  • Alport syndrome: SNHL + nephritis + eye abnormalities (X-linked; COL4A5 mutation)
• Infections: congenital rubella (now rare), CMV (most common congenital infection causing hearing loss)

• Presbycusis (age-related hearing loss): most common cause of SNHL; high-frequency loss first (4-8 kHz) → gradual progression to lower frequencies; bilateral, symmetric; stria vascularis degeneration + outer hair cell loss; aggravated by noise exposure and cardiovascular disease; no treatment; hearing aids and cochlear implants
• Noise-induced hearing loss (NIHL): second most common cause; classically 4 kHz notch on audiogram (maximum damage at 4 kHz due to resonance of the external canal); from industrial noise, concerts, firearms; permanent above a certain exposure threshold; OSHA regulations 85 dB-TWA limit; prevention: hearing protection
• Sudden SNHL (SSHL): acute loss >30 dB over ≤3 days in 3 consecutive frequencies; usually unilateral; etiology often idiopathic (presumed viral or vascular); urgent treatment: oral or intratympanic corticosteroids (within days); spontaneous recovery in 50-60%; workup: MRI to exclude acoustic neuroma (vestibular schwannoma)
• Acoustic neuroma (Vestibular Schwannoma): benign CN VIII tumor (Schwann cells of vestibular nerve); presents with unilateral progressive SNHL + tinnitus; vertigo uncommon; bilateral = neurofibromatosis type 2 (NF2); MRI with gadolinium diagnostic; treatment: radiosurgery (gamma knife), microsurgical excision, or observation
• Meniere's disease: episodic SNHL (low frequency initially), tinnitus, aural fullness, vertigo
• Ototoxic drugs:
  • Aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, neomycin): cochleotoxic; prefer serum level monitoring; gentamicin preferentially vestibulotoxic vs. tobramycin cochleotoxic; irreversible hair cell damage
  • Cisplatin and carboplatin: dose-dependent, cumulative cochleotoxicity; high-frequency loss; may be partially prevented by sodium thiosulfate
  • Loop diuretics (furosemide, ethacrynic acid): usually reversible
  • Salicylates (aspirin) at high doses: reversible tinnitus and hearing loss
  • Quinine: antimalarial; hearing loss + tinnitus
  • Vancomycin (especially in combination with aminoglycosides)
• Autoimmune inner ear disease: rapidly progressive bilateral SNHL (weeks to months); may fluctuate; responds to corticosteroids; systemic autoimmune disease in 30%
• Hypothyroidism: reversible SNHL; check TSH in unexplained hearing loss
• Syphilis: any stage; low-frequency SNHL; fluctuating; treat with high-dose IV penicillin

Mixed Hearing Loss

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TINNITUS

• Pulsatile tinnitus (synchronous with heartbeat): suggests vascular cause (arteriovenous malformation, glomus tumor, carotid stenosis, intracranial hypertension); must be investigated with MRI/MRA
• Non-pulsatile (tonal or white noise): most common; associated with SNHL; mechanism poorly understood; involves central auditory cortex reorganization

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EVALUATION OF HEARING LOSS

Audiologic Testing

• Tests hearing threshold at frequencies 250 Hz to 8000 Hz
• Threshold plotted on audiogram in decibels (dB HL)
• Normal: 0-25 dB HL; Mild loss: 26-40 dB; Moderate: 41-55 dB; Moderately severe: 56-70 dB; Severe: 71-90 dB; Profound: >90 dB

• Measures middle ear compliance (mobility of tympanic membrane) as a function of air pressure
• Type A: normal; Type B: flat = middle ear effusion or tympanic membrane perforation; Type C: negative pressure = Eustachian tube dysfunction; Ad: high compliance = ossicular discontinuity

• Stapedius muscle contraction in response to loud sound; tests CN VII, CN VIII, and brainstem
• Absent reflex: ossicular fixation (otosclerosis), CN VII or VIII lesion

• Objective assessment of the auditory brainstem pathway (waves I-V)
• Wave V latency prolongation: indicates retrocochlear pathology (acoustic neuroma, MS)
• Used in newborn screening and in patients who cannot cooperate

• Sounds generated by outer hair cell motility; measured in the ear canal
• Present in normal hearing; absent in cochlear hearing loss >~35 dB
• Universal newborn hearing screening

• Speech recognition threshold (SRT): lowest level at which 50% of two-syllable words (spondees) correctly identified
• Word recognition/discrimination score: percentage of monosyllabic words correctly repeated at suprathreshold level; poor (<70%) despite corrected thresholds = retrocochlear (neural) pathology

Signs and Symptoms Suggestive of Hearing Loss (Table 36-2)

• Speaking louder than usual
• Difficulty understanding speech, especially in background noise or on telephone
• Asking for repetition frequently
• Tinnitus
• Increasing TV volume
• Difficulty localizing sounds
• Social withdrawal

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EAR DISEASE

Otitis Externa (Swimmer's Ear)

• Diffuse infection of the external auditory canal; predominantly bacterial (Pseudomonas aeruginosa, S. aureus)
• Precipitants: water exposure (swimming), trauma (cotton swabs), humid climate, narrow canals, eczema
• Symptoms: otalgia (ear pain, worsened by moving the auricle or pressing on the tragus - pathognomonic movement sign), itching, purulent discharge, canal edema
• Treatment: topical antibiotic-corticosteroid drops (ciprofloxacin-hydrocortisone or neomycin-polymyxin-hydrocortisone); wick placement if canal severely swollen; keep ear dry

• Life-threatening extension of OE into the temporal bone and skull base
• Almost exclusively in diabetics and immunocompromised patients
• Organism: Pseudomonas aeruginosa
• Severe otalgia + granulation tissue at the bony-cartilaginous junction + CN VII palsy (facial nerve involvement)
• CT/MRI: osteomyelitis of skull base; technetium bone scan highly sensitive
• Treatment: prolonged IV anti-pseudomonal antibiotics (ciprofloxacin or antipseudomonal beta-lactam); surgical debridement; hyperbaric oxygen as adjunct
• Mortality up to 50% in severe cases

Acute Otitis Media (AOM)

• Middle ear infection; most common in children 6 months to 2 years
• Pathogens: S. pneumoniae (most common), H. influenzae (most common in non-severe cases, important with amoxicillin resistance), M. catarrhalis (beta-lactamase positive, usually self-limiting)
• Predisposed by Eustachian tube dysfunction (children have shorter, more horizontal ET), URI, daycare, bottle feeding, secondhand smoke, pacifier use
• Diagnosis: otoscopy - bulging, opacified, erythematous tympanic membrane with decreased mobility (pneumatic otoscopy)
• Symptoms: ear pain (otalgia), fever, irritability, tugging at ear, hearing loss, preceding URI
• Watch and wait approach: most cases in children >2 years resolve without antibiotics; prescribe analgesics first; reserve antibiotics for <2 years, bilateral AOM, otorrhea, severe symptoms
• Antibiotic: amoxicillin 80-90 mg/kg/day first-line; if failure: amoxicillin-clavulanate; if penicillin allergy: cefdinir or cefuroxime; if severe allergy: azithromycin (less effective)
• Complications: acute mastoiditis, meningitis, brain abscess, lateral sinus thrombosis, facial nerve palsy, labyrinthitis

Otitis Media with Effusion (OME / Glue Ear)

• Fluid in the middle ear without signs of acute infection; common after AOM
• Bilateral often; hearing loss (conductive); in children, can impair speech and language development
• Spontaneous resolution in most cases within 3 months
• Tympanometry: type B (flat) curve
• Treatment if persistent (>3 months with hearing loss): myringotomy with tympanostomy tube (grommets) - surgical drainage; hearing aids are alternative

Acute Mastoiditis

• Extension of AOM into mastoid air cells → osteomyelitis of mastoid
• Rare complication; post-antibiotic era; still occurs
• Symptoms: postauricular pain, swelling, erythema; displaced auricle (ear pushed forward and outward); fever; preceding or concurrent AOM
• CT scan: clouding of mastoid cells, destruction of mastoid trabeculae (coalescent mastoiditis)
• Treatment: IV antibiotics (amoxicillin-clavulanate or ceftriaxone); myringotomy; if no improvement or coalescent: cortical mastoidectomy (surgical)
• Complications: lateral sinus thrombosis, meningitis, subdural empyema, epidural abscess, Bezold's abscess (extension into neck)

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CHAPTER 37 - NOSE AND THROAT DISORDERS / UPPER RESPIRATORY INFECTIONS

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SINUS SYMPTOMS AND RHINITIS

• Common cold (most common)
• Allergic rhinitis (see Ch. 363)
• Vasomotor rhinitis: non-allergic; triggered by temperature changes, humidity, strong odors, spicy food
• Rhinitis medicamentosa: rebound nasal congestion from prolonged topical decongestants (oxymetazoline); limit nasal decongestants to <3-5 days
• Drug-induced: aspirin, NSAIDs, beta-blockers
• Autoimmune: granulomatosis with polyangiitis (GPA/Wegener's) - saddle-nose deformity, bloody discharge, c-ANCA/PR3-ANCA positive
• CSF rhinorrhea: unilateral clear discharge; β2-transferrin test diagnostic; usually post-traumatic
• Foreign body: children, unilateral purulent discharge
• Gastroesophageal reflux (referred)
• Sinonasal tumor (unilateral obstruction)

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ACUTE SINUSITIS (ACUTE RHINOSINUSITIS)

• Most cases (~99%) are caused by respiratory viruses (rhinovirus, influenza, parainfluenza, adenovirus)
• Bacterial sinusitis: <2% of all sinusitis; pathogens: S. pneumoniae, H. influenzae, M. catarrhalis
• Despite this, antibiotics are prescribed at >70% of sinusitis office visits - massive overprescription
• Only ~20-50% of patients actually meet criteria for antibiotic treatment

• Purulent nasal discharge, nasal congestion, facial pain/pressure, hyposmia/anosmia
• Fever, postnasal drip, halitosis, maxillary toothache, cough, fatigue, ear fullness
• Risk factors: age 45-65, smoking, asthma, air travel, allergies

• Complications suspected (orbital, intracranial)
• Chronic or recurrent cases
• Atypical presentation or immunocompromised

1. Persistent symptoms without improvement for ≥10 days, OR
2. Symptoms that initially improved then worsened (double-sickening pattern), OR
3. Onset with severe symptoms: fever ≥39°C + facial pain + purulent discharge ≥3-4 days (simultaneous severe symptoms)

• Viral sinusitis (most cases): saline nasal irrigation (most evidence-based intervention), topical nasal corticosteroids (e.g., mometasone, fluticasone), analgesics; decongestants (limited use); antihistamines only if allergic component
• Bacterial sinusitis: first-line: amoxicillin-clavulanate (875/125 mg twice daily × 5-7 days); NOT amoxicillin alone (high H. influenzae beta-lactamase); penicillin allergy: doxycycline or levofloxacin/moxifloxacin
• Fluoroquinolones reserved for treatment failure or severe allergy

• Orbital: preseptal cellulitis → orbital cellulitis/abscess → proptosis, ophthalmoplegia (emergency; IV antibiotics + CT; may need surgical drainage)
• Intracranial: meningitis, epidural/subdural empyema, brain abscess, cavernous sinus thrombosis
• Cavernous sinus thrombosis: headache + fever + unilateral proptosis → bilateral → cranial nerve palsies (III, IV, V, VI) + septicemia; CT/MRI venography; IV antibiotics + anticoagulation (controversial)
• Osteomyelitis of frontal bone: Pott's puffy tumor (subperiosteal abscess with frontal bone osteomyelitis from frontal sinusitis)

• Mucorales (Mucormycosis) and Aspergillus
• Exclusively in: uncontrolled diabetes, neutropenia, transplant, hematologic malignancy, AIDS
• EMERGENCY - rapidly progressive, can extend intracranially within days
• Symptoms: severe facial pain, fever, nasal discharge/bleeding, rapid progression to cranial nerve palsies, orbital involvement, proptosis, black eschar on palate/nasal septum (pathognomonic of Mucor)
• Diagnosis: nasal endoscopy with biopsy + gadolinium-enhanced MRI (preferred)
• Treatment: urgent surgical debridement + liposomal amphotericin B (Mucor); voriconazole (Aspergillus); control diabetes/immunosuppression
• Mortality without treatment: near 100%

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CHRONIC SINUSITIS

• Chronic rhinosinusitis without nasal polyps (CRSwNP-)
• Chronic rhinosinusitis with nasal polyps (CRSwNP): bilateral grape-like polyps from medial turbinates; associated with asthma + aspirin-exacerbated respiratory disease (AERD) = Samter's triad (asthma + nasal polyps + aspirin sensitivity); also associated with allergic fungal rhinosinusitis

• Nasal saline irrigation (large volume, twice daily): most evidence-based
• Topical intranasal corticosteroids (backbone of treatment)
• Short course of systemic corticosteroids for acute exacerbations or polyps
• Antibiotics: prolonged (3-12 weeks) macrolide antibiotics (azithromycin, roxithromycin) for anti-inflammatory effect (particularly in low-IgE endotype)
• Endoscopic sinus surgery (FESS): for patients failing medical therapy; opens sinus drainage pathways, removes polyps; good outcomes especially with focal disease
• Biologics (monoclonal antibodies): for severe uncontrolled CRS with nasal polyps refractory to standard treatment:
  • Dupilumab (anti-IL-4Rα/IL-13): FDA-approved; most evidence; reduces polyp size and improves quality of life
  • Mepolizumab (anti-IL-5), omalizumab (anti-IgE)

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SORE THROAT AND PHARYNGITIS

• Pharyngitis (viral or bacterial)
• Peritonsillar abscess
• Retropharyngeal abscess
• Submandibular space infection (Ludwig's angina)
• Epiglottitis
• Thyroiditis
• Gastroesophageal reflux
• Tumors (persistent sore throat in adult = rule out malignancy)

Streptococcal Pharyngitis (Strep Throat)

• Caused by Group A beta-hemolytic Streptococcus (GAS) - S. pyogenes
• Only common cause of pharyngitis that needs antibiotic treatment
• Goals of antibiotic therapy: reduce symptoms, prevent spread, prevent suppurative complications (peritonsillar abscess, retropharyngeal abscess, otitis media, mastoiditis, sinusitis), and prevent non-suppurative complications (rheumatic fever - most important; post-streptococcal glomerulonephritis is NOT preventable by antibiotics)

• Sudden onset sore throat, fever ≥38°C, tonsillar exudate, tender anterior cervical lymphadenopathy
• Absence of cough (important negative predictor of strep vs. viral)

• Score 0-1: do NOT test or treat (very low probability)
• Score 2-3: rapid antigen test (RADT); treat if positive
• Score 4: treat empirically without testing (in adults, pre-test probability high)

• Rapid Antigen Detection Test (RADT): sensitivity 70-90%, specificity >95%; result in minutes; if negative in child with high suspicion, confirm with throat culture
• Throat culture: gold standard; takes 24-48 hours; not needed if RADT positive
• IMPORTANT: do NOT use RADT/culture to test for carrier state (GAS can be colonized without causing disease)

• Penicillin V (500 mg twice daily × 10 days) or amoxicillin (500 mg twice daily × 10 days) - first-line; GAS has NEVER developed penicillin resistance
• Benzathine penicillin G (1.2 million units IM × 1): for poor adherence; important in rheumatic fever prevention in endemic areas
• Penicillin allergy: azithromycin (5 days) or first-generation cephalosporin (cephalexin × 10 days) if non-anaphylactic allergy
• Treat within 48 hours of onset for maximum symptom benefit and rheumatic fever prevention

• Rheumatic fever risk after untreated GAS pharyngitis: ~0.3-3% in epidemic settings
• GAS is the ONLY bacterium that causes rheumatic fever (via molecular mimicry - antibodies against M-protein cross-react with cardiac antigens)
• Rheumatic fever now rare in developed countries due to improved living conditions and widespread antibiotics
• Secondary prophylaxis after documented rheumatic fever: long-term benzathine penicillin G IM every 3-4 weeks (duration depends on carditis involvement)

• Peritonsillar abscess (quinsy): most common deep neck space infection; pus between tonsillar capsule and pharyngeal constrictor; trismus (jaw clenching), muffled "hot potato" voice, uvula deviation away from abscess, fever; treatment: needle aspiration or I&D + antibiotics + tonsillectomy (delayed)
• Retropharyngeal abscess: behind pharynx; neck stiffness, dysphagia, drooling; dangerous - can compress airway; CT scan; IV antibiotics + surgical drainage
• Ludwig's Angina: bilateral submandibular space infection, usually from dental source; submandibular swelling, trismus, drooling, "wooden floor of mouth"; airway emergency - can obstruct rapidly; IV antibiotics + surgical drainage + early airway management
• Lemierre's syndrome: septic thrombophlebitis of the internal jugular vein from oropharyngeal infection (usually F. necrophorum); fever + neck tenderness + septic pulmonary emboli; CT diagnosis; prolonged antibiotics (metronidazole + beta-lactam) ± anticoagulation

Non-Streptococcal Pharyngitis

• Classic triad: pharyngitis (severe, exudate) + marked posterior cervical lymphadenopathy + splenomegaly (50%)
• Palatine petechiae, gelatinous/edematous uvula; hepatomegaly + elevated LFTs
• Rash: 3-10% baseline; if given ampicillin/amoxicillin → 90% develop maculopapular rash (not a true allergy)
• Diagnosis: Monospot test (heterophile antibodies; sensitivity 85%, lower in early disease); EBV-specific antibodies (VCA IgM/IgG, EA, EBNA - more specific)
• CBC: lymphocytosis with atypical lymphocytes (Downey cells) >10%
• Treatment: supportive (rest, analgesics); avoid contact sports for ≥4 weeks (splenic rupture risk); corticosteroids for severe tonsillar enlargement causing airway compromise; antiviral drugs (acyclovir) do NOT shorten illness significantly

• Gray-white pseudomembrane that BLEEDS when removed (unlike candida); bull-neck appearance; toxin causes: cardiac arrhythmias (myocarditis), neurologic complications (bulbar palsy, ascending motor neuropathy)
• Treat with antitoxin (diphtheria antitoxin) + penicillin/erythromycin; notify public health
• Prevention: DTaP vaccination (primary) + Tdap booster (adults)

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EPIGLOTTITIS

• Tripod position: patient leans forward, hands on knees, neck extended ("sniffing" position) to maximize airway
• "Hot potato" muffled voice
• Drooling (cannot swallow secretions)
• Severe throat pain, dysphagia, dyspnea
• Stridor (inspiratory) in late stages

• Clinical suspicion is paramount - do NOT attempt to examine the oropharynx in suspected epiglottitis (can precipitate complete obstruction)
• Lateral neck X-ray: "thumbprint sign" (enlarged epiglottis); obtain only in stable adult
• Laryngoscopy: direct visualization of "cherry-red" epiglottis; only in controlled setting with airway backup

• Airway first: endotracheal intubation by most experienced available person (intensivist/anesthesia); if cannot intubate → surgical airway (cricothyrotomy)
• IV antibiotics: ceftriaxone + rifampin (or ampicillin-sulbactam); adjust based on cultures
• Corticosteroids: commonly used (decrease edema), but no RCT evidence

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LARYNGITIS

• Hoarseness is the cardinal symptom; also aphonia (loss of voice), cough, throat clearing, low-grade fever
• Most common cause: viral URI (rhinovirus, parainfluenza, influenza)
• Bacterial: uncommon; S. pyogenes, Moraxella
• Treatment: voice rest (whisper is actually harmful - creates tension); humidification; hydration; NSAIDs; avoid irritants (smoking, shouting); antibiotics only if bacterial signs
• Duration: typically resolves in 7-10 days

• GERD (most common cause of chronic laryngitis in adults): posterior laryngeal erythema, cobblestoning; treat with PPI
• Vocal cord polyps/nodules (vocal misuse)
• Malignancy (squamous cell carcinoma of larynx): persistent hoarseness >3 weeks in a smoker or heavy drinker = laryngoscopy mandatory to exclude cancer
• Functional dysphonia
• Laryngeal papillomatosis (HPV 6, 11)

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CHAPTER 38 - ORAL MANIFESTATIONS OF DISEASE

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DISEASES OF THE TEETH AND PERIODONTAL STRUCTURES

Tooth Anatomy

• Enamel: hardest body substance; covers crown; vulnerable to acid demineralization
• Dentin: majority of tooth; denser than bone; sensitive to pain
• Pulp: vascular and nerve supply; enclosed in dentin
• Cementum: covers the root
• Periodontal ligament: anchors tooth to alveolar bone
• Gingival sulcus: 1-3 mm depth; deeper = periodontal disease

Dental Caries

• Infectious process caused principally by Streptococcus mutans (also Lactobacillus)
• S. mutans colonizes dental plaque biofilm → metabolizes sugars → produces lactic acid → demineralizes enamel
• Most common sites: occlusal fissures, interproximal (between teeth), cervical (at gumline - especially in elderly and dry mouth)
• Progression: enamel caries → dentin (pain with sweets/cold) → pulpitis (reversible: pain resolves promptly; irreversible: spontaneous, prolonged, throbbing pain) → pulp necrosis → periapical abscess
• Treatment: remineralization (fluoride, early lesions), restoration (fillings), root canal, extraction
• Periapical abscess: can erode into alveolar bone (osteomyelitis), drain via gum-boil (parulis), spread to deep neck spaces (submandibular, sublingual, parapharyngeal) → Ludwig's angina (bilateral floor of mouth infection - airway emergency)
• Cavernous sinus thrombosis: can result from spread of dental infection (maxillary teeth) via pterygoid venous plexus or inferior ophthalmic vein → fever, headache, proptosis, CN III/IV/V/VI palsies

Periodontal Disease

• Gingivitis: reversible inflammation limited to gingival tissue; caused by plaque; presents as red, swollen, bleeding gums; treated with scaling, better oral hygiene
• Periodontitis: progressive, irreversible destruction of periodontal ligament + alveolar bone → tooth loss; bacterially-driven (gram-negative anaerobes: P. gingivalis, T. forsythia)
• Systemic associations of periodontitis:
  • Preterm birth and low birth weight
  • Cardiovascular disease (endothelial inflammation, bacteremia)
  • Diabetes (bidirectional: DM worsens periodontitis; periodontitis worsens glycemic control)
  • Rheumatoid arthritis
  • Respiratory infections (aspiration of periodontal bacteria)

• Painful, ulcerating gingival infection; necrosis of interdental papillae; metallic taste; foetor oris (terrible oral odor); "punched-out" interdental papillae
• Caused by Fusobacterium + oral spirochetes (Vincent's organisms)
• Associated with: smoking, stress, immunosuppression, poor nutrition, HIV
• Treatment: mechanical debridement + metronidazole + hydrogen peroxide rinses + improved hygiene

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DISEASES OF THE ORAL MUCOSA

Aphthous Ulcers (Canker Sores) - Most Common Oral Ulcers

• Painful, shallow ulcers with white/gray fibrinous base and red halo
• Affect ~20% of general population; recurrent
• Classification: minor (most common: <1 cm, heal in 1-2 weeks), major (>1 cm, heals in weeks with scarring), herpetiform (multiple, tiny 1-3 mm ulcers - do NOT recur on keratinized mucosa unlike herpes)
• Etiology: multifactorial; stress, trauma, foods (tomatoes, citrus), nutritional deficiencies (B12, folate, iron), hormonal, autoimmune
• Recurrent aphthous stomatitis + systemic features → consider: Behçet's disease (oral + genital ulcers + uveitis + skin lesions), IBD (Crohn's), celiac disease
• Treatment: topical corticosteroids (triamcinolone acetonide in orabase), topical anesthetics (lidocaine), tetracycline mouth rinses (reduces frequency); severe cases: colchicine, thalidomide

Herpes Simplex (HSV-1)

• Primary herpetic gingivostomatitis: most common primary infection in children; fever, malaise, extensive painful vesicles/ulcers on gingiva, mucosa, lips, tongue; cervical lymphadenopathy; resolves in 1-2 weeks
• Recurrent herpes labialis (cold sores): reactivation at vermilion border (labialis) or, in immunosuppressed, intraorally; preceded by prodromal tingling/burning; vesicles → crust
• Intraoral recurrences in normal hosts: only on KERATINIZED mucosa (hard palate, attached gingiva) - distinguishes from aphthous (non-keratinized)
• Treatment: acyclovir, valacyclovir; topical docosanol (OTC); in immunocompromised: IV acyclovir

Oral Candidiasis (Thrush)

• Caused by Candida albicans (most common) or other Candida species
• Presents as white plaques that can be scraped off, leaving an erythematous, bleeding surface
• Forms:
  • Pseudomembranous (classic thrush): white patches on buccal mucosa, tongue, palate
  • Erythematous: red patches; often under dentures
  • Angular cheilitis (perleche): fissuring and redness at corners of mouth
  • Chronic hyperplastic (leukoplakia-like): cannot be scraped off
• Predisposing factors: antibiotics (disrupt oral flora), inhaled corticosteroids (rinse mouth after use), dry mouth (xerostomia), dentures, immunosuppression (HIV, transplant, chemotherapy), diabetes, nutritional deficiency
• HIV indicator condition: recurrent/severe thrush in adults without clear cause = test for HIV
• Treatment: nystatin (oral suspension/troches) for mild; fluconazole 100-200 mg/day × 7-14 days for moderate-severe or immunocompromised

Leukoplakia vs. Erythroplakia

• White patch on oral mucosa that cannot be scraped off and cannot be attributed to any other condition
• Predominantly on buccal mucosa, tongue, floor of mouth
• Biopsy mandatory to exclude dysplasia/carcinoma
• Malignant transformation rate: ~1-2% overall; higher for lesions on floor of mouth, ventral tongue, and those with dysplasia
• Risk factors: tobacco, alcohol, chronic irritation

• Red velvety patch that cannot be attributed to another cause
• Much higher malignant transformation risk than leukoplakia (40-50% already dysplastic/carcinoma in situ at biopsy)
• Any red oral mucosal lesion in an adult must be biopsied promptly

Oral Cancer (Squamous Cell Carcinoma)

• Most common oral malignancy; accounts for ~3% of all cancers
• Risk factors: tobacco (smoking and smokeless) + alcohol (synergistic when combined); HPV infection (HPV-16) - now major risk factor, especially for oropharyngeal (base of tongue, tonsils) cancer
• Common sites: floor of mouth, ventral/lateral tongue, soft palate (highest risk); lip (usually lower lip)
• Symptoms: painless ulcer/lump that does NOT heal in >3 weeks, indurated (firm) edges; erythroplakia; leukoplakia; cervical lymphadenopathy
• Any oral ulcer or lesion that does not heal in 3 weeks requires biopsy
• Treatment: surgical resection (± reconstruction) + radiation ± chemotherapy; HPV-positive oropharyngeal cancers have significantly better prognosis

Pigmented Lesions of Oral Mucosa (Table 38-2)

White Lesions of Oral Mucosa (Table 38-3)

• Bilateral, symmetric white reticular (lacey, Wickham's striae) pattern on buccal mucosa; may also have erosive/bullous/atrophic forms
• Association with Hepatitis C infection
• Drug-induced oral lichenoid reactions: NSAIDs, ACE inhibitors, beta-blockers, antimalarials
• Erosive lichen planus: painful, can bleed; malignant transformation risk 1-3%
• Treatment: topical corticosteroids; systemic for severe cases; treat underlying Hep C

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NONDENTAL CAUSES OF ORAL PAIN

• Temporomandibular joint (TMJ) disorder: jaw pain + clicking + headache + limited opening
• Salivary gland disease (sialadenitis, sialolithiasis - stone in duct)
• Trigeminal neuralgia: lancinating, electric-shock facial pain along V1/V2/V3; triggered by chewing, speaking, touching
• Burning mouth syndrome: burning pain without visible lesion; postmenopausal women; may be neuropathic; treat with clonazepam, antidepressants
• GERD: posterior tooth erosion, "acid-etching" of teeth
• Hematologic: aphthous-like ulcers in neutropenia, thrombocytopenic bleeding

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ORAL MANIFESTATIONS OF SYSTEMIC DISEASE

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HIGH-YIELD CLINICAL PEARLS - SECTION 4 SUMMARY

Red Flags That Change Management Immediately

Drug-Induced Ototoxicity - Must Know

Weber and Rinne Quick Reference

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